Enhanced lipid utilization in infants receiving oral L-carnitine during long-term parenteral nutrition

Fourteen infants requiring long-term total parenteral nutrition but able to tolerate small quantities of enteral feedings were randomized into carnitine treatment and placebo control groups. All infants had received nutritional support devoid of carnitine. Plasma carnitine levels and observed plasma lipid indices were not different before supplementation. Under standardized, steady-state conditions, 0.5 g/kg fat emulsion (intralipid) was administered intravenously over 2 hours both before and after infants received 7 days of continuous nasogastric or gastric tube L-carnitine (50 mumol/kg/day) or placebo. Plasma triglyceride, free fatty acid, acetoacetate, beta-hydroxybutyrate, and carnitine concentrations were observed at 0 (start of lipid infusion), 2, and 4 hours for pre- and post-treatment periods, and in addition at 6 and 8 hours after carnitine supplementation. Infants receiving carnitine had significantly greater beta-hydroxybutyrate plasma concentrations (P less than 0.05) and carnitine (P less than 0.001) at 0, 2, 4, 6, and 8 hours, and greater plasma acetoacetate concentrations (P less than 0.05) at 2, 4, 6, and 8 hours, compared with controls. Twenty-four-hour urinary carnitine excretion was very low for both groups before supplementation; after supplementation, excretion was higher (P less than 0.05) in the carnitine group. No significant differences were found between groups for plasma triglyceride or free fatty acid concentrations at any observation period. This study demonstrated enhanced fatty acid oxidation, as evidenced by increased ketogenesis, with L-carnitine supplementation in infants receiving long-term total parenteral nutrition.     

Oral L-carnitine supplementation in low-birth-weight newborns: a study on neonates requiring combined parenteral and enteral nutrition

Effect of L-carnitine supplementation on plasma ketone body (KB) and triglyceride (TG) concentrations was studied in ten premature infants requiring combined enteral and parenteral nutrition. At the second week of life (9 to 14 days of age) the infants were randomly divided into two groups. Five of them (plasma carnitine value, 33.77 +/- 2.48 mumol/l; mean +/- SEM) received oral L-carnitine supplementation (60 mumol/kg daily) added to pasteurized pooled human milk for seven consecutive days; additional five (plasma carnitine value, 36.70 +/- 5.19 mumol/l) served as controls. Composition of the daily diet was nearly constant in the study period. On the seventh day, prior to an Intralipid infusion, plasma carnitine and ketone body levels were significantly increased in the supplemented group as compared to controls or to previous values of the same group. In response to lipid infusion the fat load induced ketone body production was significantly higher in the supplemented group as compared to controls, whereas the triglycerides reached higher levels in the control group. It is suggested that L-carnitine supplementation in low-weight newborns promotes ketone body formation from endogenous stores as well as from exogenous fat supply, and thus may enhance triglyceride utilization.     

Impairment of lipid emulsion metabolism associated with carnitine insufficiency in premature infants

Carnitine status and its relation to lipid metabolism were determined in 11 premature infants (less than 34 weeks of gestation) receiving parenteral nutrition. Intravenous administration of lipid emulsion increased serum concentrations of free fatty acids at 2, 4, and 8 h after infusion. Despite this increase, serum levels of ketone bodies remained low, reaching only 40 to 45% of levels in full-term infants receiving enteral feeds. In premature infants, levels of plasma total and free carnitine were about half those in full-term infants and were not altered by lipid infusion. The results indicate limited potential for lipid emulsion as a source of energy in premature infants, possibly because carnitine insufficiency restricts fatty acid oxidation.     

Carnitine deficiency in premature infants receiving total parenteral nutrition

Carnitine plays a significant role in fatty acid utilization and ketone body production. Its availability is especially important during the immediate postnatal period. To determine whether low birth weight infants who cannot be orally fed are at risk of developing carnitine deficiency, we compared the carnitine blood levels and urinary excretion of 12 premature infants (Group A) receiving total parenteral nutrition (TPN) with those of 8 infants of similar gestational age and birth weight (Group B) who received carnitinecontaining milk formulas.In Group A, serum levels of total and free carnitine fell after 5 days of carnitine-deficient parenteral nutrition, and urinary excretion was significantly reduced. Serum levels and urinary excretion increased after the onset of oral feedings. The control Group B exhibited no significant changes in carnitine blood levels between the first and fifth days of life, but did show a later increase. Children in Group A had lower carnitine blood levels compared to those in Group B on the fifth day of life.These findings suggest that premature infants are not able to synthesize enough carnitine to maintain blood levels, and that carnitine deficiency can occur following TPN. Further investigation of metabolic consequences secondary to deficient carnitine intake in premature infants is necessary before carnitine supplementation should be considered.     

Postheparin plasma lipases and carnitine in infants during parenteral nutrition

Lipoprotein lipase is the rate-limiting factor for hydrolyzing triglycerides to glycerol and fatty acids. Carnitine is a cofactor in the transport of long-chain fatty acids through the mitochondrial membrane for oxidation. To assess these determinants of fat utilization during total parenteral nutrition, lipoprotein and hepatic lipase activities and carnitine concentrations of nine newborn infants, operated on because of gastrointestinal anomalies during the first day of life, were measured with specific methods. Total parenteral nutrition was built up in 3 days whereafter the infants received 3 g/kg of fat at a constant rate of infusion for 24 h/day. Lipoprotein lipase activity of post-heparin plasma increased from 14 to 35 mumol free fatty acids/ml/h during parenteral nutrition whereas hepatic lipase activity remained unchanged at 40 mumol free fatty acids/ml/h. Serum free carnitine and acylcarnitine levels decreased significantly during parenteral nutrition; urinary excretion of carnitine decreased also. In addition, serum cholesterol and phospholipids increased markedly during parenteral nutrition whereas serum triglycerides, free fatty acids, and blood beta-hydroxybutyrate remained unchanged. Serum apolipoprotein A-I concentrations were unaltered, apolipoprotein A-II underwent a transient increase, and apolipoprotein B increased monotonically during parenteral nutrition. The results suggest that under the present circumstances neither lipoprotein lipase activity nor carnitine resources are rate-limiting for the utilization of fat in newborn infants during total parenteral nutrition.     

L-carnitine supplementation of a soybean-based formula in early infancy: plasma and urine levels of carnitine and acylcarnitines

The absence of carnitine in the diet of normal infants results in marked reduction of plasma carnitine levels. In order to evaluate the effects of L-carnitine supplementation of soybean formula, plasma and urine levels of free carnitine and acylcarnitine were compared in infants receiving carnitine-free soybean protein-based formula and the same formula supplemented with 50 and 250 nmol/ml L-carnitine. In infants receiving soybean formula with 50 nmol/ml L-carnitine, the plasma levels of free carnitine were not significantly different from those in infants receiving formula with 250 nmol/ml L-carnitine; however, urine levels of free carnitine were significantly increased when the infants received formula with 250 nmol/ml L-carnitine. In normal full-term infants, supplementation of soybean formula with 50 nmol/ml L-carnitine was sufficient to maintain normal plasma levels that were comparable to breast-fed infants.     

Carnitine deficiency

Carnitine facilitates the transport of activated fatty acids across the mitochondrial membrane and regulates energy metabolism through regeneration of intramitochondrial coenzyme A. In carnitine deficiency it may be a limiting factor for fatty acid oxidation and ketogenesis. Primary myopathic carnitine deficiency is characterized by low carnitine concentrations usually restricted to muscle; whereas systemic carnitine deficiency shows decreased concentrations in other organs and plasma as well. The latter condition features recurrent metabolic crises similar to those seen in Reye's syndrome and nonketotic hypoglycemia. A therapy with L-carnitine should be undertaken, but does not always prove effective. Similar symptoms may be caused by defects in beta-oxidation, Krebs cycle or respiratory chain enzymes. The conditions may be associated with secondary carnitine deficiency. Patients with organic acidurias exhibit an increased excretion of carnitine esters and an insufficiency of free carnitine. Carnitine supplementation may ameliorate the metabolic disturbance. Secondary carnitine deficiency has also been described in patients receiving chronic valproic acid therapy. Hemodialysed chronic renal patients may benefit from L-carnitine therapy and show improvement of their hyperlipidemia. Nutritional carnitine deficiency can be primarily expected in premature infants receiving a carnitine free diet, since these infants have an impaired capacity for carnitine biosynthesis.     

Effect of carnitine on lipid metabolism in the neonate. II. Carnitine addition to lipid infusion during prolonged total parenteral nutrition

The effect of carnitine administration on lipid metabolism and carnitine and acylcarnitine plasma values of newborn infants, given total parenteral nutrition for the first 7 days of life, was studied during a 4-hour infusion of Intralipid. An increase in plasma concentrations of total carnitine, free carnitine, and short-chain and long-chain acylcarnitine was found, but no significant change in triglycerides, free fatty acids, glycerol, or beta-hydroxybutyrate plasma values was noted, as compared with values obtained without carnitine administration. Moreover, the low free carnitine and short-chain and long-chain acylcarnitine plasma levels found in newborn infants after 7 days of total parenteral nutrition did not seem to impair the utilization of infused lipids. The results support the concept that the relation between the carnitine pool and lipid metabolism can be influenced by intravenous glucose infusion. Low carnitine plasma concentrations do not necessarily signify a depletion of body carnitine, and sufficient tissue carnitine concentrations can probably maintain good lipid utilization for an extended period.     

Carnitine concentrations in the milk of different species and infant formulas

Carnitine concentrations were measured in the milk of sheep, cows, goats, and horses, in human milk of term and preterm infants and in European infant formulas. There were significant species' differences in carnitine milk content. Acylcarnitine concentrations ranged from 13 to 47% of total carnitine. This may be related to differences in maternal and/or mammary gland metabolism. The concentration of long-chain acylcarnitine in milk was under 1% in all investigated species. In cow's milk, there was a decrease in acylcarnitine concentration during the first 2 months of lactation. In human milk, carnitine concentrations did not change during the 1st month postpartum, but maternal plasma carnitine concentrations increased and plasma concentrations of acylcarnitine were always lower than those in simultaneously sampled milk. Milk carnitine concentrations in mothers of premature infants were not different from those in mothers of term infants. European formulas based on cow's milk contained somewhat more carnitine than human milk. However, very low carnitine concentrations were found in soy-based or protein hydrolysate formulas. This may lead to nutritional carnitine deficiency in infants receiving these formulas without carnitine supplementation.     

Effects of oral L-carnitine supplementation in low-birth-weight premature infants maintained on human milk

Effects of oral L-carnitine supplementation on fat and protein metabolism have been studied in 20 low-birth-weight premature infants (mean weight at birth 1.519 g, range 1,200-1,880 g) fed with pooled pasteurized human milk. Throughout 7 consecutive days, started at various postnatal ages (range 10-33 days) infants were fed exclusively with milk containing 300 nmol/ml L-carnitine as added supplement. The amount of extra carnitine intake ranged from 42.6 to 72.0 mumol/kg/day. Until day 5 of supplementation there was a continuous increase in the daily urinary excretion of total carnitine, which levelled off thereafter, corresponding approximately to 50% of the extra L-carnitine intake, indicating that a part of the supplement was retained by the body. Total, free and esterified carnitine levels were significantly elevated in the plasma at the end of the study period. The increased levels of acylcarnitines in plasma and urine indicate that the carnitine supplement was taken up by tissues and entered the intermediary metabolism. Plasma triglyceride level was decreased, whereas 3-hydroxybutyrate level was increased at the end of supplementation, indicating an enhanced fat utilization. Plasma and urine analysis also revealed an altered nitrogen handling. There was a marked decrease in plasma urea level as well as a significant fall in the urea and total N excretion, with a trend of decrease in excretion of 3-methylhistidine, suggesting a reduced amino acid and protein catabolism during L-carnitine supplementation.     

Absence of responses in energy metabolism and respiratory quotient to carnitine infusion in premature infants

Plasma levels of total, free and acylcarnitine, as well as oxygen consumption and respiratory quotient were determined in premature infants maintained at neutral temperature. The effects on these parameters of intravenous infusion of 24 mg/kg/day carnitine were studied. Total, free and acylcarnitine increased and the acyl/free carnitine ratio decreased significantly during the four-hour study period. Resting heat production and respiratory quotient remained practically unchanged throughout the study period, indicating that in the face of carnitine sufficiency exogenous carnitine did not influence whole body heat production and substrate utilization pattern in premature infants. Further examinations in carnitine depleted infants will be required to clarify the regulatory role of carnitine in neonatal fatty acid metabolism and non-shivering thermogenesis.     

Metabolic effects in neonates receiving intravenous medium-chain triglycerides

The effects of two lipid emulsions, one with 50% each of medium-chain and long-chain triglycerides, and a long-chain triglycerides lipid emulsion as a control, were evaluated for lipid and carnitine metabolism and respiratory quotient when given to neonates after major surgery during a short period of total parenteral nutrition. Each group included 10 neonates, and all tolerated the total parenteral nutrition well. The relative contents of linoleic acid and alpha-linolenic acid increased in all lipid esters in plasma and adipose tissue in both groups, indicating that the content of these fatty acids is sufficient even in the medium-chain triglycerides emulsion. The serum concentration of ketones was within normal limits. Free fatty acids in plasma did not increase in either group. The total plasma carnitine concentration decreased in both groups but the distribution of free carnitine and acylcarnitine did not change. The total muscle carnitine did not change significantly but the ratio of acylcarnitine to free carnitine tended to increase in muscle in the treatment group, probably an effect of the medium-chain triglyceride supplementation. CONCLUSIONS: The two groups displayed the same fatty acid pattern in plasma and adipose tissue and the same respiratory quotient during the treatment period. Regarding carnitine status, essentially the same changes were seen in the two groups. However, discrete changes were seen in muscle tissue in the treatment group.     

Renal conservation of carnitine by infants and adults: no evidence of developmental regulation

To determine the efficiency of renal conservation of carnitine in infants, urinary carnitine excretion was measured at intervals in 10 infants while plasma carnitine concentration was manipulated by supplementing carnitine-free formula with 0 microM, 140 microM and 280 microM L-carnitine. As carnitine supplementation increased from 0 microM to 280 microM, fractional excretion of free carnitine increased tenfold from 0.6% to 6.0%; fractional excretion of acylcarnitine esters increased to a lesser degree (10.5-15.6%). At all supplementation levels fractional excretion of acylcarnitine esters was significantly greater than fractional excretion of free carnitine. We conclude that free and esterified carnitine are handled differently in the infant kidney. Results in infants were compared to previously reported data for adults. Mean fractional excretions of total, free and esterified carnitine by infants (7.2%, 5.4% and 12.7%, respectively) were similar to those by adults (6.5%, 5.0% and 15.0%). Thus, renal losses of carnitine apparently do not account for the low plasma carnitine concentrations observed in infants fed carnitine-free formulas.     

Plasma and tissue levels of lipids, fatty acids and plasma carnitine in neonates receiving a new fat emulsion

This study was undertaken to compare Intralipid® with a new fat emulsion containing gamma-linolenic acid and carnitine, named Pediatric Fat Emulsion 4501, in neonates with regard to lipid and carnitine metabolism over a short period of total parenteral nutrition. There were 10 neonates in each group and they tolerated the total parenteral nutrition well. In spite of the gamma-linolenic acid supplementation in the new emulsion, arachidonic acid decreased significantly in plasma lipid esters and adipose tissue in both groups after 5 d of treatment. Also, there was a decrease in plasma docosahexaenoic acid which was more pronounced in the treatment group. The relative percentage values of linoleic and linolenic acids in adipose tissue were increased, indicating that newborns have a rapid accretion of fatty acids. Plasma triglycerides were effectively cleared during the periods without fat infusion. In the group that received Pediatric Fat Emulsion 4501 the means of both free and total plasma carnitine concentrations increased significantly, whereas they tended to decrease in the Intralipid® group.     

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??Abstracts?? L-carnitine is an essential vitamin for the transfer of long-chain fatty acids from the cytosol into mitochondria for β-oxidation. Carnitine deficiency results in impaired energy production from long-chain fatty acids, especially during periods of fasting or stress. Primary carnitine deficiency due to defective carnitine transporter OCTN2 caused by SLC22A5 gene mutations is an autosomal recessive disorder of mitochondrial β-oxidation. It is a rare but treatable disease of metabolic myopathies. The onset could occur in the patients with primary carnitine deficiency at any ages under a broad clinical spectrum. In infancy, metabolic decompositions occurred triggered by fasting or common illnesses such as upper respiratory tract infection or gastroenteritis. Hypoketotic hypoglycemia, metabolic acidosis, hyperammonemia and hyperuricemia were common findings. Some patients may be combined with cardiac arrhythmia, heart failure, fatty liver and brain damage. From children to adults, progressive or acute cardiomyopathy and skeletal myopathy have been reported worldwide. Early recognition of the disease and treatment with L-carnitine supplementation are keys to life-saving.     

原发性肉碱缺乏症与心肌病

左旋肉碱（又称左卡尼汀,简称肉碱）是协助长链脂肪酸从细胞质转运至线粒体进行β氧化的重要物质。肉碱缺乏导致长链脂肪酸代谢障碍,尤其是在饥饿和应激情况下导致能量产生不足。原发性肉碱缺乏症属常染色体隐性遗传病,SLC22A5基因突变导致肉碱转运蛋白OCTN2缺陷,引起线粒体脂肪酸β氧化障碍,是少数可治疗的代谢性肌肉病之一。原发性肉碱缺乏症患者可在任何年龄阶段起病,轻重不一,个体差异显著。婴儿期可在上呼吸道感染、胃肠炎等普通疾病诱发下出现急性代谢紊乱,常见低酮症性低血糖、代谢性酸中毒、高尿酸血症,一些患儿伴心律紊乱、心功能衰竭、脂肪肝、脑损害。在儿童至成人可表现为慢性进行性或急性心肌病及骨骼肌肌肉病,早期诊断、左卡尼汀支持治疗是挽救生命的关键。     

Urinary medium-chain acylcarnitines in medium-chain acyl-CoA dehydrogenase deficiency, medium-chain triglyceride feeding and valproic acid therapy: sensitivity and specificity of the radioisotopic exchange/high performance liquid chromatography method.

To determine the sensitivity and specificity of detecting urinary medium-chain acylcarnitines for the diagnosis of MCAD deficiency, 114 urine specimens from 75 children with metabolic diseases and controls were analyzed in a blinded fashion using a radioisotopic exchange/HPLC method. All 47 patients with MCAD deficiency were correctly diagnosed using the criterion hexanoylcarnitine or octanoylcarnitine peak areas larger than those of other medium-chain acylcarnitines. The majority of them were tested during the asymptomatic state without L-carnitine loading. Four patients with other defects of fatty acid oxidation and three patients receiving valproic acid had a similar acylcarnitine excretion pattern. To further examine the specificity of the method, eight infants receiving a diet enriched with medium-chain triglycerides and 13 additional patients receiving valproic acid were studied. Most of these also tested positive for MCAD deficiency by the above criterion. Analysis by a new gas chromatographic-mass spectrometric procedure revealed that octanoylcarnitine, not valproylcarnitine, was the most abundant medium-chain carnitine ester excreted by a patient treated with valproic acid. Quantitation of urinary hexanoylcarnitine and octanoylcarnitine showed considerable overlap among patients with MCAD deficiency and those receiving valproic acid or a medium-chain triglyceride-enriched diet. MCAD deficiency can be reliably detected in urine specimens by this method without the need for prior carnitine loading. However, other defects in fatty acid oxidation must be differentiated from MCAD deficiency, and a history of medium-chain triglyceride or valproic acid administration must be considered if the diagnosis of MCAD deficiency is sought through analysis of urinary acylcarnitines.     

Blood levels of total carnitine and lipid utilization with and without carnitine supplementation in newborn infants

Postnatal changes of the plasma carnitine level were compared in orally and parenterally fed newborn infants. As expected, in contrast to the increasing plasma level of carnitine in infants fed with human milk, a gradual and significant fall was observed during parenteral feeding. Next, the effect of carnitine supplementation on the elimination rate of an Intralipid load was tested. The increased disappearance rate of triglycerides associated with the exogenously administered carnitine suggested an increased lipid utilization during the carnitine supplemented period of parenteral nutrition.     

Nutritional follow-up of the breastfeeding premature infant after hospital discharge

In summary, fortification of human milk may be beneficial in preterm infants, particularly those born at less than 34 weeks' gestation or less than 1800 g birth weight, during and after initial hospitalization. This fortification after hospital discharge is more crucial for infants who cannot consume ad libitum quantities of breast milk, have poor growth, or have abnormalities in the biochemical screen of nutritional status. Although data indicate that in-hospital, short-term gains in growth and mineral status are achieved, information is fragmentary regarding the influence on long-term growth and neurodevelopmental outcomes of feeding supplemented human milk. Also, no data are available on outcomes when providing these mixtures to premature infants after hospital discharge. It is recommended that a nutritional survey be accomplished before and approximately 1 month after discharge and that fortification or supplementation be initiated if an infant is failing to achieve normal growth and biochemical measures of nutrition.     

Plasma carnitine and breast milk carnitine intake in premature infants

Ten premature infants with a mean gestational age of 29 weeks (range, 27-32) and a mean birth weight of 1,294 g (range, 930-2,300) and without complications at birth were studied during the first 14 days after birth. Their breast milk intake was recorded and the carnitine content determined in each daily portion. During the first week, the daily mean carnitine intake was low and increased to 6-7 mumoles/kg and day during the second week. Breast milk carnitine concentration ranged from 17 to 148 mumoles/L. Plasma carnitine and its derivatives did not change during the observation period. No relationship was found between the individual cumulative breast milk carnitine intake and total plasma carnitine levels or between carnitine and its derivatives and nonesterified fatty acids or 3-OH-butyrate. The urinary carnitine excretion, in millimoles of carnitine per mole of creatinine, was higher during the second week. In other studies, declining plasma carnitine levels have been observed in premature infants on total parenteral nutrition. The results from this study indicated that premature infants without complicating disorders were able to maintain their plasma carnitine levels.